Tuberculosis (TB) has been a major worldwide threat to human health for several thousands of years. TB caused by Mycobacterium tuberculosis is an infectious disease of the lung caused by infection through exposure to air-borne M. tuberculosis bacilli. These bacilli are extremely infectious and it has been estimated that currently approximately one-third of the world population (2 billion people) are infected. It has been further estimated that TB kills over 2 million people worldwide on an annual basis. Only 5 to 10% of the immunocompetent humans are susceptible to TB, and over 85% of them will develop the disease exclusively in the lungs, while HIV-infected humans may also develop systemic diseases that will more easily lead to death.
Approximately 90% of M. tuberculosis-infected humans will not develop the disease. However, in these latently infected individuals, the bacilli can survive for many years and become reactivated, for instance, in the case of a weakened immune system, such as after an HIV infection. Due to the latent nature, infected individuals generally have to be treated by administration of several antibiotics for up to 12 months. This is not a very attractive treatment in general and due to costs and the possible occurrence of multi-drug resistance, it is also not a very effective treatment in most developing countries.
One relatively successful TB vaccine has been developed: the bacilli Calmette-Guerin (BCG) vaccine was generated in the early years of the twentieth century and was first given to individuals in 1921. The BCG vaccine is an attenuated strain of bacteria based on a Mycobacterium bovis isolate obtained from a cow. It is a relatively safe vaccine, which is easily, and rather inexpensively, produced. In the year 2000, BCG vaccination covered 86% of the world population. However, the vaccine appears to not be extremely effective for adult pulmonary TB and many regions in developing countries still have very high rates of TB, despite the BCG vaccine programs. It has been estimated that BCG vaccine prevents only 5% of all vaccine-preventable deaths by TB (Kaufmann, 2000).
Due to the rather low protection rate of the BCG vaccine in general and due to the specific protection with respect to childhood and disseminated TB, more efforts were put in the development of new, more broadly applicable, vaccines against TB that were based on other systems and knowledge acquired in other fields, e.g., vaccination against other tropical infectious diseases and HIV (Wang & Xing, 2002).
Different approaches were taken to develop new TB vaccines, ranging from subunit vaccines and DNA vaccines to modified mycobacterium strains. Moreover, recombinant viral-based vaccines were also generated, enabling the transfer of M. tuberculosis antigens to antigen-presenting cells through gene delivery vehicles, such as Modified Vaccinia Ankara (MVA) vectors and replication-defective adenovirus vectors.
Naked DNA vaccines against TB have been described in WO 96/15241 (see also EP 0792358), whereas many reports describe the use of numerous antigens from Mycobacterium tuberculosis in either recombinant or purified form for their application in vaccines: WO 95/01441, WO 95/14713, WO 96/37219, U.S. Pat. No. 6,599,510, WO 98/31388, WO 98/44119, WO 99/04005, WO 99/24577, WO 00/21983, WO 01/04151, WO 01/79274, WO 2004/006952, US 2002/0150592. The use of fusion proteins comprising different TB antigens has also been suggested. See WO 98/44119, EP 0972045 and EP 1449922, disclosing the use of a fusion polypeptide between ESAT-6 and MPT59 (MPT59 is also referred to as Ag85B or the 85B antigen).
Despite such efforts in generating a vaccine against TB that ensures both a strong cellular and a strong humoral response, as well as a long-lasting high protection rate, no such vaccine is yet available.